A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol with potential anti‐obesity effects

• Published in: British journal of pharmacology Vol. 169; no. 4; pp. 784 - 793
• Main Authors: Bisogno, Tiziana, Mahadevan, Anu, Coccurello, Roberto, Chang, Jae Won, Allarà, Marco, Chen, Yugang, Giacovazzo, Giacomo, Lichtman, Aron, Cravatt, Benjamin, Moles, Anna, Di Marzo, Vincenzo
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2013
• Subjects: 2‐arachidonoylglycerol; Animals; Anti-Obesity Agents - administration & dosage; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; anti‐obesity effects; Arachidonic Acids - antagonists & inhibitors; Arachidonic Acids - metabolism; Behavior, Animal - drug effects; Biosynthesis; cannabinoid; Cell Line; Cercopithecus aethiops; diacylglycerol; Dose-Response Relationship, Drug; Endocannabinoids - antagonists & inhibitors; Endocannabinoids - metabolism; Energy Intake - drug effects; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glycerides - antagonists & inhibitors; Glycerides - metabolism; Glycerophospholipids - administration & dosage; Glycerophospholipids - pharmacology; Glycerophospholipids - therapeutic use; Humans; Hypothalamus - drug effects; Hypothalamus - enzymology; Hypothalamus - metabolism; inhibitor; Lipoprotein Lipase - antagonists & inhibitors; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; Medical research; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; Obesity; Obesity - drug therapy; Obesity - enzymology; Obesity - metabolism; Oleic Acids - administration & dosage; Oleic Acids - pharmacology; Oleic Acids - therapeutic use; Organophosphonates - administration & dosage; Organophosphonates - pharmacology; Organophosphonates - therapeutic use; Rats; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Rodents; serine lipase; Sterol Esterase - antagonists & inhibitors; Sterol Esterase - metabolism; Themed Section: Cannabinoids 2012, Part Two
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.12013

Background and Purpose The development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol (2‐AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects. Experimental Approach Three new fluorophosphonate compounds O‐7458, O‐7459 and O‐7460 were synthesized and characterized in various enzymatic assays. The effects of O‐7460 on high‐fat diet intake were tested in mice. Key Results Of the new compounds, O‐7460 exhibited the highest potency (IC50 = 690 nM) against the human recombinant DAGLα, and selectivity (IC50 > 10 μM) towards COS‐7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity‐based protein profiling confirmed that O‐7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off‐target’, that is, the serine hydrolase KIAA1363. O‐7460 did not exhibit measurable affinity for human recombinant CB1 or CB2 cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O‐7460 (10 μM) reduced 2‐AG levels. When administered to mice, O‐7460 dose‐dependently (0–12 mg·kg−1, i.p.) inhibited the intake of a high‐fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight. Conclusions and Implications O‐7460 might be considered a useful pharmacological tool to investigate further the role played by 2‐AG both in vitro and in vivo under physiological as well as pathological conditions. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐4 & http://dx.doi.org/10.1111/bph.2012.167.issue‐8